Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.
Audesh Bhat, G. Lahane, R. Pandita et al.· Trends in Cancer· 0 citations
Ectopic deposition of calcium oxalate in the parenchyma (nephrocalcinosis) or as stones in the collecting system (nephrolithiasis) causes inflammation and oxidative stress in renal tissue. Receptor interacting serine/threonine kinase 2 (RIPK2) is a well-known mediator of oxidative stress and inflammation. However, its role in nephrocalcinosis or nephrolithiasis remains unexplored. Normal rat kidney-52E (NRK-52E) and primary renal cells were treated with calcium oxalate-monohydrate (COM) to induce nephrocalcinosis like pathological changes. siRNAs and commercially available inhibitor was used to block RIPK2's activity. Oxidative stress, inflammation, apoptosis, crystal adhesion, and changes in cell morphology were measured as endpoint markers. Exposure to COM but not to adenine, H2O2, and high-glucose significantly upregulated RIPK2 levels and induced oxidative stress, intracellular-calcium overload, and mitochondrial dysfunction. This was accompanied by nuclear factor-kappa B (NF-κB) pathway activation, increased levels of pro-inflammatory cytokines, decreased levels of anti-inflammatory cytokines, and enhanced apoptosis and epithelial-mesenchymal transition (EMT). RIPK2 silencing or pharmacological inhibition effectively mitigated these pathological changes and restored levels of antioxidant enzymes. Mechanistically, RIPK2 inhibition disrupted the NF-κB/TGF-β1 signaling and reduced CaOx crystal adhesion. Preliminary data from our previously conducted in vivo CaOx mouse model study confirmed the CaOx-induced RIPK2 upregulation. Our data strongly supports the involvement of RIPK2 in CaOx-induced renal cell damage.
G. Lahane, Arti Dhar, Audesh Bhat· Biochemical Pharmacology· 0 citations
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